Malignant gliomas represent the single most costly and morbid neoplasm per-capita. The prognosis for patients with these tumors has been largely unchanged by advances in surgery, radiation therapy and drug design. Our proposal provides an integrated effort to translate to clinical human trials laboratory advances in the design of virus vectors for the delivery of drug-enhancing genes to tumor cells. These studies explore intracerebral, arterial and peripheral delivery systems. Three Projects and three Cores are united as a resource for the brain-tumor Consortium (NABTT) to provide a template for the systematic evaluations of vectors systems for gene therapy of intracerebral tumors in rats and patients with glioblastomas. Extensive studies of vector delivery are explored in rodents bearing 9L or D-74 brain tumors. The establishment of vector efficacy is judged using a rigid template prior to extensive toxicity testing in primates. Based on discussions with the FDA we view as collaborative strengths our interactions with the Somatix Corporation (for GMP-grade vectors), the uniform biostatistic overview of all Projects and Cores as well as the participation of members of the New England Primate Center for clinical, pathologic and immunopathologic monkey studies. By providing protocols for rigorous preclinical and clinical studies, we formulate a scientific basis for the conduct and interpretation of small population gene therapy trials. Sequential studies are designed to provide high titers of safe replication-competent and incompetent vectors derived from retrovirus, herpes simplex virus type I (HSV) and herpes- amplicon vectors. By focusing on expression of enzymes which activate pro-drugs, (the HSV-thymidine kinase gene for ganciclovir, and cytochrome P450 genes for cyclophosphamide and methyl PCNU), we also create a model to explore in-situ drug delivery. Drug studies will be supported by a pharmacology Core for analysis and modeling of activated drugs. All studies will supported by histologic studies of gene expression and neuropathology, as well as the molecular characterization of tumors. Our program defines a rational and scientific means to evaluate the potential of gene therapy for brain tumors.